A hollow fiber blood treatment apparatus that utilizes a permselective membrane has been widely used for extracorporeal circulation, hemodialysis, supplying oxygen to blood during cardiotomy, plasma separation, or the like. A polysulfone-based blood treatment membrane has been widely used in the field of a blood treatment membrane such as a dialysis membrane, a gas exchange membrane, and blood component separation membrane. In recent years, the membrane has been not only served as a separation membrane, but also attempted to reduce oxidative stress that adversely affects a long-term dialysis patient. As an approach of the attempt, removal of peroxides that cause oxidative stress, or rejuvenating the antioxidant ability of a living body can be given. For example, Patent Documents 1 and 2 disclose a blood treatment membrane having excellent antioxidant properties, and the membrane is obtained by coating the surface of a previously formed membrane with vitamin E that exhibits various physiological actions such as in vivo antioxidant action, biological membrane stabilizing action, platelet aggregation suppressing action and the like.
However, since the blood treatment membrane is coated with vitamin E after assembling an artificial organ, the production process becomes complex so that productivity decreases. Moreover, since the membrane is coated with vitamin E only on the surface thereof, a sufficient effect to a substance that may permeate the membrane cannot be achieved. Therefore, it is desirable that a lipophilic antioxidant be provided over the entire membrane.
In order to improve the above problems, a method of producing a hollow fiber blood treatment membrane, comprising using a core liquid that contains vitamin E, or immersing the blood treatment membrane in a bath that contains vitamin E so that the vitamin E is present over the blood treatment membrane material entirely, and the resultant blood treatment membrane has been proposed (Patent Document 3). This method is effective for streamlining of the production process and enabling vitamin E to be provided over the membrane material entirely. However, vitamin E cannot be applied to the inside of the polymer skeleton that forms the membrane base material, and therefore elution of a low-molecular-weight substance that is undesirable for a human body and caused by oxidative decomposition of the polymer forming the membrane during long-term storage of the blood treatment membrane, or breakage of the blood treatment membrane due to a decrease in elongation of the membrane may not be prevented.
As another approach oxidative stress may also be thought to alleviate by preventing an oxidation reaction that occurs during dialysis. In particular, it is considered to be useful to prevent entry of endotoxins from a dialysate that are very toxic to a living body. Specifically, when endotoxins have entered into blood and a body, oxygen radicals are produced and released from phagocytes as part of biological defense mechanism.
It is effective to use a hydrophobic membrane that easily adsorbs endotoxins in order to solve this problem. However, a conventional hydrophobic membrane cannot be used due to the poor blood compatibility thereof. For example, a hollow fiber membrane that is produced by causing a hydrophilic polymer to adhere to only the inner surface of the hollow fiber membrane comprising a polymer alloy of a polysulfone and a polyarylate so that the inner surface exhibits antithrombogenicity while the highly hydrophobic outer surface adsorbs and removes endotoxins, has been disclosed (Patent Document 4). This hollow fiber membrane is effective for preventing entry of endotoxins from a dialysate since the polymer alloy has high hydrophobicity. However, since the hydrophobicities of the porous area and the outer surface are too high, air can be passed through to only a small extent, and this adversely affects diffusion permeability through the membrane. Moreover, the above hollow fiber membrane is ineffective for the cause of oxidative stress other than endotoxins. Furthermore, since a hydrophilic polymer that serves as a pore-forming agent during membrane formation by a wet process is not used, it is difficult to control the pore diameter. This makes it difficult to control permeability.
A method of producing a hollow fiber membrane formed of a polysulfone and a hydrophilic polymer that includes providing the outer surface of the membrane with hydrophobicity to increase endotoxin adsorption properties by reducing the content of the hydrophilic polymer in the entire membrane material, and applying vitamin E or the like that exhibits anti-thrombogenic properties on only the inner surface of the membrane to provide blood compatibility, has been disclosed (Patent Document 5). However, since the hydrophilic polymer is present on the outer surface of the membrane, a problem due to loss of adsorptivity easily occurs even if the endotoxin permeability can be temporarily decreased. Moreover, since the amount of hydrophilic polymer present on the outer surface of the membrane is small, air is insufficiently passed through. According to the finding of the present inventors, when producing a membrane so that the outer surface of the membrane has a low hydrophilic polymer concentration, the hydrophilic polymer concentration on the inner surface of the membrane inevitably decreases, and thus the anti-thrombogenic properties become really insufficient. Patent Document 5 discloses applying vitamin E on the inner surface of the membrane material to improve platelet adsorption properties as a more preferred embodiment. However, Patent Document 5 does not take account of the distribution of vitamin E providing in the membrane material and an improvement in endotoxin adsorption properties by utilizing the distribution of vitamin E in the membrane material.
A blood treatment membrane which vitamin E is provided in the entire membrane including in the inside of the membrane base material by adding vitamin E to a membrane-forming raw spinning solution, and a method of producing the same have been disclosed (Patent Document 3). According to this membrane, since vitamin E is present everywhere in the entire membrane material, a surface state differing from that of a conventional blended membrane made from polymers such as a polysulfone and a hydrophilic polymer can be obtained so that endotoxin adsorption properties may be expected to increase by controlling skillfully. According to the finding of the present inventors, however, when a large amount of vitamin E is included in order to provide the outer surface of the membrane with sufficient hydrophobicity, the mechanical strength of the blood treatment membrane decreases to an impractical level. On the other hand, when the content of vitamin E is reduced to a level so as to maintain the practical strength of the membrane, the outer surface of the membrane cannot be provided with sufficient hydrophobicity. This is considered to be because vitamin E is segregated at the microdomain interface of the base polymer so that the intermolecular interaction of the base polymer is adversely affected. A membrane which vitamin E is coated on the entire surface of the membrane as in Patent Document 1 can prevent a decrease in strength. However, when the membrane already structurally-formed is subjected to a post-treatment such as coating, a significant change in the surface state due to a decrease in pore size and surface deposition by the coated material may occur.
This makes it difficult to employ such a membrane.
As described above, when modifying a blood treatment membrane formed from a polysulfone-based resin as a base polymer with a lipophilic antioxidant, it is very difficult for the resulting membrane to provide excellent antioxidant properties and long-term storage stability, a capability of preventing invasion of endotoxins through the outer surface of the membrane, and practical strength. However, a blood treatment membrane produced using a polysulfone-based resin as a base polymer has been increasingly demanded. Therefore, a polysulfone-based blood treatment membrane that exhibits the above properties and has high productivity and a method of producing the same have been strongly desired.
Patent Document 1: JP-A-H07-178166
Patent Document 2: JP-A-2000-296931
Patent Document 3: JP-A-H09-66225
Patent Document 4: JP-A-H10-151196
Patent Document 6: JP-A-2000-254222